In recent studies, we have: 1) successfully imaged activation in the human trigeminal pathway; 2) demonstrated the occurrence of sensitization along peripheraland central trigeminovascular pathways following induction of intracranial pain in our animal model of migraine; and 3) documented the presence and extent of cutaneous allodynia during migraine using quantitative sensory testing in human subjects. Based on these studies, we hypothesize that migraine pain is associated with sensitization of the following neuronal populations: meningeal nociceptors in the trigeminal ganglion (TG), trigeminovascular neurons in the spinal trigeminal nucleus (SpV), and neurons in the thalamus. The objective of the current proposal is to test this hypothesis using functional magnetic resonance imaging (fMRI). In Specific Aims 1-3we will determine whether, during migraine attacks, innocuous thermal and mechanical stimuli produce different fMRI signal changes in the TG, SpV, and thalamus in patients exhibiting (a) no signs of cutaneous allodynia (Specific Aim 1); (b) cephalic allodynia restricted to the periorbital area (Specific Aim 2); and (c) whole body (cephalic plus extracephalic) allodynia (Specific Aim 3). Specific Aim 4 will determine whether allodynia during migraine is associated with changes in fMRI signal in the periaqueductal gray, an area that has been implicated in migraine pathophysiology. The preliminary data demonstrate our ability to detect significant induction of fMRI BOLD signal in TG, SpV, and Th following skin stimulation in healthy volunteers and in migraine patients. Preliminary studies show that mechanical and thermal skin stimulation during migraine increase fMRI signal in TG, SpV and thalamus in a manner that depends on the presence and type of allodynia. This grant proposal represents a unique collaborative effort between researchers with expertise in pain imaging, migraine, and quantitative sensory testing to examine a new hypothesis for the pathophysiology of migraine, a neurological disorder that affects more than 35 million women and men in the US.